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Immunity and pathogenesis in persistent viral infection

English title Immunity and pathogenesis in persistent viral infection
Applicant Pinschewer Daniel
Number 149340
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.01.2014 - 31.12.2016
Approved amount 610'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Experimental Microbiology

Keywords (5)

Persistent infection; Virus; Hepatitis; T cells; Antibody

Lay Summary (German)

Lead
Weltweit gibt es 350 bzw. 170 Millionen Menschen, welche Träger der Hepatitis B bzw. Hepatitis C Virus (HBV, HCV) Infektion sind. Weitere rund 30 Millionen leben mit HIV. Leberzirrhose und Leberkrebs oder eine tödliche Immunschwächekrankheit können daraus resultieren. Nur ein kleiner Prozentsatz der Betroffenen weltweit hat Zugang zu wirksamer Therapie, und für HCV und HIV gibt es bis heute keine Schutzimpfung.
Lay summary

Hintergrund: Vom Körper gebildete Antikörper stellen einen zentralen Pfeiler jeden Impfschutzes dar doch verstehen wir nur unzureichend wie diese tatsächlich wirken und so können wir ihr Potenzial bestenfalls unvollständig zur Impfung nutzen. Analoges gilt für sogenannte „Killer T Zellen“, welche vom Körper zur Abwehr gegen Viren wie HBV oder HCV hergestellt werden. Man würde solche Zellen gerne zur Heilung dieser Krankheiten einsetzen und den betroffenen Patienten verabreichen. Hierfür ist aber ein besseres Verständnis ihres Wirkprinzips unabdingbar.

Ziel dieses Forschungsprojektes: Dieses Forschungsprojekt soll grundlegende Mechanismen ergründen mittels derer i) Antikörper uns gegen Virusinfektionen schützen, und ii) sogenannte „Killer T Zellen“ unseren Körper von einer Virusinfektion befreien können. Hierzu werden unter anderem genetisch verändertes Lymphozytäres Choriomeningitis Virus (LCMV) und Vesikuläres Stomatitis Virus verwendet. Zum Studium der molekularen Grundlagen dieser biologischen Vorgänge werden des weiteren gentechnisch veränderte Mausstämme eingesetzt, welche im Infektions-Experiment  die Bedeutung einzelner Abwehrmechanismen eindeutig nachweisen lassen.

Bedeutsamkeit: Persistierende Viruserkrankungen sind global von kaum zu überschätzender Bedeutung, und neue Strategien zu deren Bekämpfung sind dringend von Nöten. Die Anwendung von modernster molekularbiologischer Methodik, in Kombination mit relevanten Infektionsmodellen beim Tier, ermöglichen es grundlegend neue Mechanismen der Körperabwehr und Ihres Wirkungsprinzips zu entdecken. Solche Erkenntnisse sind unabdingbar um der globalen Problematik persistierender Virusinfektionen bessere präventive und therapeutische Optionen entgegensetzen zu können.

 

Direct link to Lay Summary Last update: 13.12.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival
Utzschneider DT Alfei F Roelli P Barras D Chennupati V Darbre S Delorenzi M Pinschewer Zehn (2016), High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival, in J Exp Med, 213(9), 1819-1834.
Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection
Sommerstein R Flatz L Remy MM et al. (2015), Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection, in PLoS Pathog, 11(11), e1005276.
Protective Efficacy of Individual CD8+ T Cell Specificities in Chronic Viral Infection
Johnson S Bergthaler A Graw F Flatz L Bonilla WV Siegrist C Lambert P Regoes RR Pinschewer D (2015), Protective Efficacy of Individual CD8+ T Cell Specificities in Chronic Viral Infection, in J Immunol, 194(4), 1755-1762.
T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses.
Baumann C Bonilla WV Fröhlich A Helmstetter C Peine M Hegazy AN Pinschewer DD* Löhning M (2015), T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses., in Proc Natl Acad Sci U S A, 112(13), 4056-4061.
The Nucleoprotein Is Required for Lymphocytic Choriomeningitis Virus-Based Vaccine Vector Immunogenicity
Darbre S Johnson S Kallert S Lambert PH Siegrist CA Pinschewer DD. (2015), The Nucleoprotein Is Required for Lymphocytic Choriomeningitis Virus-Based Vaccine Vector Immunogenicity, in J Virol, 89(22), 11734-11738.
Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection.
Penaloza-MacMaster P. et al. (2015), Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection., in Science, 347(6219), 278-282.

Collaboration

Group / person Country
Types of collaboration
Merkler / University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Verbeek / Leiden University Medical Center Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Kalinke / Twincore Hannover Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Löhning / Charité Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Zehn / Technische Universität München Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Weill & Reynaud / Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Marsland / University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Müller / University of Manchester Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Barouch / Harvard University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
135442 Virus-host balance and pathogenesis in persistent infection 01.09.2011 SNSF Professorships
173132 Immunity and tolerance in persistent viral infection 01.04.2017 Project funding (Div. I-III)

Abstract

Background: Estimated 350 and 170 million people worldwide are persistently infected with hepatitis B and C virus (HBV, HCV), respectively, and more than thirty million people live with HIV. Antiviral therapy is only accessible to a minority of those in need, and preventive vaccines for HCV and HIV remain unavailable. Antibodies are a key component of antiviral vaccine protection, but their mechanism of protective efficacy remains incompletely understood, thus limiting our capacity to fully harness their potential for vaccine development. Similarly, adoptive immunotherapy and therapeutic vaccination have considerable potential for curing HBV and HCV, but a refined mechanistic understanding of viral clearance from hepatocytes is needed.Working hypothesis: I) Neutralization of virus in cell culture is a surrogate for detection of protective antibody specificities, but in vivo antibody efficacy relies critically on inflammation-induced pathways for scavenging and intracellular degradation of antibody-coated virions. II) In adoptive immunotherapy, hepatic inflammation and T cell infiltration dampen viral replication in hepatocytes and limit viral dissemination. This involves type I and type II interferon signaling to infected cells, triggering distinct transcriptional programs. Elimination of infection relies, however, critically on T cell cytotoxicity, resulting in the eventual replacement of most infected hepatocytes.Experimental models and methods: We will use genetically engineered lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV) for infection and protection experiments in new and innovative gene-targeted mouse models. Recombinant antibody engineering, genome-wide transcriptome analyses, TaqMan RT-PCR, immunohistochemistry and flow cytometry will be combined with state-of-the-art immunological and virological techniques.Specific aims: We aim to investigate the following fundamental questions in immunity and pathogenesis of systemic persistent viral infection:1. Mechanisms underlying in vivo efficacy of neutralizing and non-neutralizing antiviral antibodies.2. The role of innate and adaptive immune responses in augmenting protective antibody efficacy. 3. Non-cytolytic “cure” of virus-infected hepatocytes: proof-of-principle and molecular signature. 2. IFNa/ß and IFN-? signaling in virus-infected hepatocytes: role in T cell-mediated clearance.Significance: We will combine an array of cutting-edge molecular tools and methodology and will apply them to relevant animal models of viral infection. The project therefore has potential for a quantum leap in understanding of antiviral antibody protection and T cell-mediated elimination of persisting viruses from the liver. Fundamental novel concepts in these areas are urgently needed to combat persisting viral infections of global health impact.
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